A fat storage hormone changed minds and weight of study mice.

Guojun Bu's studies show a link between fat, Alzheimer’s and obesity in genetic issues.

Their mission was to solve a small but nagging mystery of Alzheimer's disease: How would the brain's ability to store information be affected if they "turned off" the obscure protein LRP1?

But Guojun Bu and his fellow researchers were in for a surprise. As they expected, mice whose brains had been wiped of the LRP1 gene showed Alzheimer's-like memory problems. But they also started to put on weight - fast.

The mice were lethargic. They were on their way to becoming diabetic. And they didn't seem to know when to stop eating.

In other words, they were a lot like the more than 72 million Americans who are obese.

Bu, a neuroscientist at the Mayo Clinic in Jacksonville and the study's lead author, said the findings could lead to a treatment that attacks the genetic causes of obesity.

"People complain that for people who are obese, it's just a lack of self control," he said. "But this confirmed there's a strong genetic element that controls their appetite."

Or rather, reconfirmed. Scientists have long suspected that people's DNA has a profound impact on their waistlines, and a number of studies have proved them right.

Bu's research focused on leptin , a hormone that regulates fat storage. Normally, leptin is produced as the body's cells take in fat from food, sending a signal to the brain that suppresses appetite. Bu, who did the bulk of the research while with the Washington University School of Medicine in St. Louis, found that both the leptin and LRP1 receptors must work together to transmit those signals.

Researchers injected a virus into young mice to turn off the LRP1 gene in the hypothalamus, the brain's control center. After six months, there was virtually no difference between the "knock out" mice and the normal ones.

But then, the modified mice suddenly got plumper as their leptin signals faded. A year into the experiment, the mice weighed an average of about 43 grams; their counterparts, less than 30.

New potential, challenges

The results were striking because they were the opposite of what a different set of researchers had found a few years earlier while studying the effects of LRP1. In that study, however, the gene was shut off not in the brain but in the body's fat cells, and the mice ended up losing weight.

That could make it trickier to develop a therapy that targets LRP1, said David Hui, a researcher at the University of Cincinnati who was involved in the earlier study. No medicine yet developed can send a part of the body one message while telling another the complete opposite.

"Having said that," Hui added, "the importance of this study is that they have also identified the downstream signaling pathway involved. This should be immensely valuable for designing more specific targets."

The study was published in the Jan. 11 issue of the journal PLoS Biology. It was the second study that grew out of the experiment.

The first, published in December in the Journal of Neuroscience, discussed what Bu initially intended to show: Knocking out LRP1 not only made mice fat, but it also disrupted their memory.

Cholesterol, usually depicted as the body's bad guy, is critical to the maintenance of neurons. And LRP1 is one of two key receptors for the brain's cholesterol-transport system. So if it went down, Bu theorized, the neurons would lose synaptic contact with other neurons, impairing memory.

The connection between obesity and Alzheimer's isn't necessarily surprising, Bu noted. There is strong evidence that Type II diabetes, a disease often linked to obesity, is a major risk factor for developing Alzheimer's.